Clinical Trials /

Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST



Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting.

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST
  • Official Title: Phase II, Single Arm, Non-randomized and Multicenter Clinical Trial of Regorafenib as a Single Agent in the First-line Setting for Patients With Metastatic and/or Unresectable KIT/PDGFR Wild Type GIST

Clinical Trial IDs

  • NCT ID: NCT02638766


  • Gastrointestinal Stromal Tumors


regorafenibStivargaUnique arm


Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting.

Detailed Description

      The SDH complex is involved in mitochondrial Krebs cycle and defects in the succinate
      dehydrogenase (SDH) complex have identified, as previously mentioned, in KIT/PDGFR WT. This
      complex, SDH, has 4 subunits (A-D) and SDH-A or SDH-B are involved in oxidization succinate
      to fumarate. Therefore, loss of function owing to mutational inactivation leads to the
      cytoplasmic accumulation of succinate which downregulates prolyl hydroxylase. This enzyme has
      a negative regulator role of hypoxia-inducible factor 1α (HIF1α) since promotes its
      proteasomal degradation. Increased levels of HIF1α can enter the nucleus and activate the
      transcription of vascular endothelial growth factor (VEGFR)24. In fact, the VEGFR expression
      is higher in KIT/PDGFR WT than in KIT mutant GISTs25.

      Approximately 50% of KIT/PDGFR WT show high expression of insulin-like growth factor 1
      receptor (IGFR1). This expression may correlate also with the loss of SDH due to IGF
      autocrine loop26. IGFR signals through both MAPK and PI3K-AKT pathways. As previously
      mentioned, Regorafenib is able to block MAPK signaling pathway at different levels.
      Interestingly, early interstitial Cajal cell (ICC) progenitors have a phenotype of
      KITlowCD44+CD34+IGFR+ while committed lineage of progenitors have KIThighCD44+CD34-IGFR-.
      Unlike mature or more committed lineage of ICCs, the KITlowCD44+CD34+IGFR+ display resistance
      to Imatinib in spite of kit signaling pathway activation. Thus Regorafenib could gain
      advantage over Imatinib for treating KIT/PDGFR WT27,28.

      On the other hand, other subsets within of KIT/PDGFR WT as B-RAF mutants or NF1-associated
      GIST could also be sensitive to Regorafenib. In this later subset, protein expression of
      phospho-MAPK was seen in 92% of cases in a series of 25 patients29.

      Theoretically Regorafenib could also act blocking STAT3, which is activated by RET
      proto-oncogen, through RET inhibition. STAT3 is implicated as downstream pathway signal in

      Taken together, the previous data suggests Regorafenib could play a relevant role as upfront
      treatment of metastatic or unresectable locally advanced KIT/PDGFR WT GIST.

      Subjects will receive 160mg (4 tablets) of regorafenib once a day every day for 3 weeks of
      every 4 week cycle (i.e., 3 weeks on, 1 week off). The study drug will be orally

      Doses of study drug may be delayed or reduced in case of clinically significant hematologic
      and other toxicities. Toxicities will be graded using the CTCAE v 4.03. The modifications of
      regorafenib are detailed in the protocol for general event, Hand Foot Skin Reaction,
      Hypertension and drug-related liver function test abnormalities.

Trial Arms

Unique armOtherRegorafenib 160mg once a day, frequency: 3 weeks on/1 week off in cycles of 28 days
  • regorafenib

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must provide written informed consent prior to performance of study-specific
             procedures or assessments and must be willing to comply with treatment and follow-up.

             Informed Consent must be obtained prior to start of the screening process. Procedures
             conducted as part of the patient´s routine clinical management (e.g. blood count,
             imaging tests, etc.) and obtained prior to signature of informed consent may be used
             for screening or baseline purposes as long as these procedures are conducted as
             specified in the protocol.

          2. Male or female subjects ≥18 years of age

          3. Histologically confirmed GIST KIT/PDGFR wild-type, unresectable or metastatic GIST
             (confirmed by central laboratory). Paraffin-embedded tumor block must be provided by
             all subjects during screening period.

          4. Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18
             exons of PDGFR gene

          5. Subjects must have at least one measurable lesion according to RECIST v1.1 criteria. A
             lesion in a previously irradiated area is eligible to be considered as measurable
             disease as long as there is objective evidence of progression of the lesion prior to
             study enrolment.

          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          7. Adequate bone marrow, liver, and renal function as assessed by the following
             laboratory requirements conducted within 7 days of starting study treatment:

               -  Total Bilirubin ≤ 1.5 x the upper normal limit (UNL). Documented Gilbert Syndrome
                  is allowed if total bilirubin is mildly elevated (≤6mg/dl).

               -  Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x UNL
                  (≤5xUNL for subjects with liver involvement of GIST)

               -  Lipase ≤1.5 x UNL

               -  Serum Creatinine ≤ 1.5 x UNL

               -  Glomerular filtration rate (GFR) ≥ 30ml/mn/1.73 m2 according to the Modified Diet
                  in Renal Disease (MDRD) abbreviated formula.

               -  International Normalized Ratio (INR) ≤1.5xUNL and partial thromboplastin time
                  (PTT) or activated partial thromboplastin time (aPTT) ≤1.5xUNL. Subjects who are
                  being treated with an anti-coagulant, such as warfarin or heparin, will be
                  allowed to participate provided that no prior evidence of an underlying
                  abnormality in these parameters exists. Close monitoring of at least weekly
                  evaluations will be performed until INR and PTT are stable based on a pre-dose
                  measurement as defined by the local standards of care.

               -  Platelet count ≥100000mm3, hemoglobin (Hb) ≥ 9.0 g/dl, absolute neutrophil count
                  (ANC) ≥1500/mm3. Blood transfusions to meet the inclusion criteria will not be

               -  Alkaline phosphatase limit ≤ 2.5 x UNL (≤ 5x UNL for subjects with disease
                  involving the liver)

          8. Women of childbearing potential and men must agree to use adequate contraception from
             the moment of signing the Informed Consent Form until at least 3 months after the last
             study drug administration. The investigator or a designated associate is requested to
             advise the subject on how to achieve an adequate birth control. Adequate contraception
             is defined in the study as any medically recommended method (or combination of
             methods) as per standard of care.

          9. Women of childbearing potential must have a blood or urine pregnancy test performed a
             maximum of 7 days before start of study treatment, and a negative result must be
             documented before start of study treatment.

        Exclusion Criteria:

          1. Prior systemic treatment for GIST BESIDES IMATINIB. Patients that have relapsed after
             receiving imatinib during adjuvant setting and patients who are on treatment or have
             been treated with Imatinib as first line of advanced KIT/PDGFRa wild type GIST are

          2. Cancer other than GIST within 5 years prior to randomization EXCEPT for curatively
             treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder
             tumors (Ta (Non Invasive tumor), and Tis (Carcinoma In situ)).

          3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             before the start of study medication.

          4. Congestive Heart Failure New York Heart Association (NYHA) ≥ class 2.

          5. Unstable angina (angina symptoms at rest, new-onset angina, ie, within the lasts 3
             months prior to entering study) or myocardial infarction (MI) within the past 6 months
             before the start of study medication.

          6. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are

          7. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure >
             90mmHg despite optimal medical management).

          8. Subjects with pheochromocytoma.

          9. Arterial thrombotic or embolic events such as cerebrovascular accident (including
             transient ischemic attacks), or pulmonary embolism within 6 months from start of study

         10. Venous thrombotic events such as deep vein thrombosis within the 3 months before the
             start of study treatment.

         11. Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for
             Adverse Events (NCI-CTCAE) version 4.03

         12. Known history of human immunodeficiency virus (HIV) infection.

         13. Subjects with seizure disorder requiring medication

         14. Symptomatic metastasis in brain or meningeal tumors.

         15. History of organ allograft.

         16. Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding
             event ≥ NCI-CTCAE version 4.03 grade 3 or higher within 4 weeks prior to start of
             study treatment.

         17. Non-healing wound, ulcer, or bone fracture.

         18. Renal failure requiring hemo- or peritoneal dialysis.

         19. Dehydration NCI-CTCAE version 4.03 grade ≥ 1

         20. Substance abuse or medical, psychological, or social conditions that may interfere
             with the subject´s participation in the study or evaluation of the study results.

         21. Known hypersensitivity to the study drug, study drug class, or excipients in the

         22. Any illness or medical conditions that are unstable or could jeopardize the safety of
             the subject and his/her compliance in the study

         23. Interstitial lung disease with ongoing signs and symptoms at the time of screening.

         24. Subjects unable to swallow oral medication

         25. Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher (>3.5g/24hrs),
             measured by urine protein creatinine ratio on a random urine sample)

         26. Any malabsorption condition.

         27. Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution
             (whichever is higher).

         28. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version
             4.03 grade 2 dyspnea)

        NOTE: It is not necessary to demonstrate disease progression or imatinib intolerance to
        offer the study entrance.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease Control Rate
Time Frame:every 8 weeks during 36 months
Safety Issue:
Description:the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).

Secondary Outcome Measures

Measure:Progression free survival
Time Frame:every 8 weeks during 36 months
Safety Issue:
Description:Number of months without progression
Measure:Overall survival
Time Frame:Every 8 weeks during 36 months
Safety Issue:
Description:Number of months alive
Measure:Responses determined by CHOI
Time Frame:every 8 weeks during 36 months
Safety Issue:
Description:Measure tumor size
Measure:Correlation with translational research
Time Frame:After 36 months of recruitment
Safety Issue:
Description:Relation between the clinical data obtained and the data obtained from translational research
Measure:Safety (adverse events following CTCAE v4.03)
Time Frame:Every 28 days until 30 days after last dose
Safety Issue:
Description:Evaluation of adverse events following CTCAE v4.03
Measure:Early metabolic response by PET scan
Time Frame:After 1 month of starting treatment
Safety Issue:
Description:Evaluation of metabolic response to treatment
Measure:Quality of life by EORCT QLQ C30 questionnaire
Time Frame:Day 1 of each cycle. Pre-treatment administration
Safety Issue:
Description:EORCT QLQ C30 questionnaires
Measure:Quality of life by EQ-ED-5L questionnaire
Time Frame:Day 1 of each cycle. Pre-treatment administration
Safety Issue:
Description:EQ-ED-5L questionnaires


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Grupo Espanol de Investigacion en Sarcomas

Trial Keywords

  • metastatic
  • unresectable
  • KIT/PDGFR wild type GIST

Last Updated

December 19, 2019